This project focuses on analysis of the genetic controls and physiological regulators that modulate hearing loss in a population of genetically heterogeneous mice. The test population will consist of 600 animals bred as the progeny of (CAST/Ei X 129S1/SvImJ)F1 females and (C3H/HeJ X FVB/NJ)F1 males. Each mouse generated in this four-way cross is genetically unique, and a full sib to each other animal in the population. Each mouse will be tested for hearing acuity by auditory brainstem response at ages 2, 8, 14, 18 and 22 months. Half of the 600 mice will be exposed to noise-induced cochlear injury at age 14.5 months. SNP-based genotyping at each of 300 loci will provide a genomic map of loci modulating hearing acuity, its change over age, and its resistance to noise-induced damage (Aim 1). Aim 2 will test the hypothesis that hearing loss is related to, and predictable by, individual differences in cellular resistance to oxidative cytotoxic stress, using in vitro analyses of fibroblast cell lines from each tested mouse. This strategy reflects recent evidence that mutations that retard aging and extend life span in mice may do so by alterations of stress-sensitivity in multiple cell types, including fibroblasts. Aim 3 will test the hypothesis that the genes, and potentially the non-genetic factors, that modulate functional hearing loss and cellular stress resistance also affect cochlear hair cell loss and oxidative damage to cochlear structures. Aim 4 tests a series of related hypothesis concerning the effects of early-life growth, maturation, and hormone patterns on mid- and late-life stress resistance and functional outcome, including hearing loss. Aim 5 will measure a range of age-sensitive traits, including indices of immunity and visual function, to test the hypothesis that inter-individual differences in age-related hearing loss are linked to differences among mice in multiple aspects of aging. This strategy will also yield, as a useful byproduct, a great deal of genetic information about loci that modulate growth, maturation, stress resistance, cataracts, hormones, and immunity in young and older mice. The approach chosen will permit a comprehensive assessment of the extent to which age-depending alterations in hearing are molded by genetic, cellular and hormonal factors that time the aging process in mice.